The present invention relates to an agent for the prophylaxis and treatment of liver disease. More specifically, the present invention relates to an agent for the prophylaxis and treatment of liver diseases, which agent comprises a compound having a Rho kinase inhibitory activity, and most particularly, the present invention relates to an agent for the prophylaxis and treatment of liver diseases caused by the activation of hepatic stellate cells.
Liver diseases are caused by various factors, such as virus infection, excessive intake of alcohol, bilharziasis and the like. These initial etiologic factors cause gradual replacement of liver parenchyma with connective tissues, leading to fibrogenesis in progress. The progress of fibrogenesis in the liver inhibits hemodynamics, and impairs the process of liver regeneration, making the disease state of liver failure irreversible, which often results in transition to hepatic cirrhosis and hepatic cancer.
The hepatic stellate cell (also called fat storing cell) is a major cell that produces extracellular matrix both in normal liver and liver with advanced fibrogenesis. In a general state, the hepatic stellate cell is supplied as a vitamin A storage site. This cell is in a resting state, scarcely shows a proliferation acticity, and is limited to be an element to constitute connective tissues. In a wounded liver and a fibrogenetic liver, however, the hepatic stellate cell loses lipid droplet thereof and changes to a cell such as myofibroblast. This myofibroblast-like cell is an xe2x80x9cactivatedxe2x80x9d cell exhibiting a high proliferation acticity, and synthesizes a large amount of collagen and other extracellular matrix proteins, and expresses smooth muscle type xcex1-actin and desmin. Therefore, the hepatic stellate cell is considered to play a major role in fibrogenesis of the liver, and further in the etiology of of hepatic fibrosis (Shimizu, I. et. al., Gut 44(1), 127-136 (1999)).
Accordingly, a substance that inhibits activation of hepatic stellate cell is considered to be effective for the prophylaxis and treatment of fibrogenesis of the liver, which is caused by the activation of hepatic stellate cell.
As a low molecular weight compound having an inhibitory action on the activation of hepatic stellate cell, only a histone deacetylase inhibitor represented by trichostatin and estradiol have been heretofore reported (JP-A-10-114681, Shimizu, I. et al., ibid.).
In WO98/06433, compounds of the formula (I) to be mentioned later and certain isoquinolinesulfonamide derivatives are described as compounds having a Rho kinase inhibitory activity, and as compounds having a Rho kinase inhibitory activity, is isoquinoline derivatives have also been reported (Naunyn-Schmiedeberg""s Archives of Pharmacology 385(1) Suppl., R219, 1998).
A compound having a Rho kinase inhibitory activity is described in WO98/06433 as being widely useful as a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a cerebrovascular spasm suppressant, a therapeutic agent of asthma, a therapeutic agent of peripheral circulatory disturbance, a premature delivery preventive, a therapeutic agent of arterial sclerosis, an anticancer drug, an anti-inflammatory agent, an immunosuppressant, a therapeutic agent of autoimmune diseases, an anti-AIDS agent, a therapeutic agent of osteoporosis, a therapeutic agent of retinopathy, a cerebral function improver, a contraceptive drug, and a gastrointestinal tract infection preventive. However, WO98/06433 does not contain a description of its usefulness as an inhibitor of the activation of hepatic stellate cells or an agent for the prophylaxis and treatment of liver diseases, or a description to suggest such effect.
Furthermore, the compound of the formula (I) has been already known to be useful as an agent for the prophylaxis and treatment of disorders of circulatory organs such as coronary, cerebral, renal, peripheral artery and the like (e.g., a therapeutic agent of hypertension, a therapeutic agent of angina pectoris, a therapeutic agent of renal and peripheral circulation disorder, a suppressive agent of cerebrovascular contraction and the like), which is potent and long lasting, and also as a therapeutic agent of asthma (JP-A-62-89679, JP-A-3-218356, JP-A-4-273821, JP-A-5-194401, JP-A-6-41080 and WO95/28387).
The isoquinolinesulfonamide derivative described in the above-mentioned WO98/06433 is known to be effective as a vasodilating agent, a therapeutic agent of hypertension, a cerebral function improver, an anti-asthma agent, a heart protecting agent, a platelet aggregation inhibitor, a therapeutic agent of neurologic manifestation, an anti-inflammatory agent, an agent for the prevention and treatment of hyperviscosity syndrome, a therapeutic agent of glaucoma, a diminished tension agent, a motor paralysis improver of cerebral thorombosis, an agent for prevention and treatment of virus infection and transcriptional control factor inhibitor (JP-A-57-200366, JP-A-61-227581, JP-A-2-256617, JP-A-4-264030, JP-A-6-56668, JP-A-6-80569, JP-A-6-293643, JP-A-7-41424, JP-A-7-277979, WO97/23222, JP-A-9-227381, JP-A-10-45598 and JP-A-10-87491).
Moreover, the isoquinoline derivative described in the above-mentioned publication (Naunyn-Schmiedeberg""s Archives of Pharmacology 385(1) Suppl., R219, 1998) is known to be useful as an agent for the prevention and treatment of brain tissue disorder due to vasospasm (WO97/28130). However, usefulness of the compounds having a Rho kinase inhibitory activity as activators of hepatic stellate cells or an agent for the prophylaxis and treatment of liver diseases is not disclosed, and there is no description suggestive of such usefulness.
The present invention intends to solve the above-mentioned problems relating to liver diseases, particularly fibrogenesis of the liver, and aims at providing an agent for the prophylaxis and treatment of liver diseases and an activation inhibitor of hepatic stellate cells. In other words, the present invention aims at providing an agent for the prophylaxis and treatment of hepatitis, hepatic fibrosis, hepatic cirrhosis, hepatic cancer and the like.
The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems and found that a compound having a Rho kinase inhibitory activity inhibits activation of hepatic stellate cells and suppresses hepatic fibrogenesis in liver tissues, and that the compound is useful as an activation inhibitor of hepatic stellate cells and for the prophylaxis and treatment of liver diseases such as hepatitis, hepatic fibrosis, hepatic cirrhosis, hepatic cancer and the like, which resulted in the completion of the present invention.
Accordingly, the present invention provides the following.
(1) An agent for the prophylaxis and treatment of liver disease, which comprises a compound having a Rho kinase inhibitory activity.
(2) The agent for the prophylaxis and treatment of liver disease of (1) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I) 
xe2x80x83wherein
Ra is a group of the formula 
xe2x80x83in the formulas (a) and (b),
R is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or a group of the formula 
xe2x80x83wherein R6 is hydrogen, alkyl or formula: xe2x80x94NR8R9 wherein R8 and R9 are the same or different and each is hydrogen, alkyl, aralkyl or phenyl, R7 is hydrogen, alkyl, aralkyl, phenyl, nitro or cyano, or R6 and R7 in combination show a group forming a heterocycle optionally having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R1 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring, or
R and R1 in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2 is hydrogen or alkyl,
R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl or azide, and
A is a group of the formula 
xe2x80x83wherein R10 and R11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10 and R11 show a group which forms cycloalkyl in combination and l, m and n are each 0 or an integer of 1-3,
xe2x80x83in the formula (c),
L is hydrogen, alkyl, aminoalkyl, mono- or dialkylaminoalkyl, tetrahydrofurfuryl, carbamoylalkyl, phthalimidoalkyl, amidino or a group of the formula 
wherein B is hydrogen, alkyl, alkoxy, aralkyl, aralkyloxy, aminoalkyl, hydroxyalkyl, alkanoyloxy-alkyl, alkoxycarbonylalkyl, xcex1-aminobenzyl, furyl, pyridyl, phenyl, phenylamino, styryl or imidazopyridyl,
Q1 is hydrogen, halogen, hydroxy, aralkyloxy or thienylmethyl,
W is alkylene,
Q2 is hydrogen, halogen, hydroxy or aralkyloxy,
X is alkylene,
Q3 is hydrogen, halogen, hydroxy, alkoxy, nitro, amino, 2,3-dihydrofuryl or 5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl;
and Y is a single bond, alkylene or alkenylene, and
xe2x80x83in the formula (c), a broken line is a single bond or a double bond, and
R5 is hydrogen, hydroxy, alkoxy, alkoxycarbonyloxy, alkanoyloxy or aralkyloxycarbonyloxy;
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(3) The agent for the prophylaxis and treatment of liver disease of (1) or (2) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (Ixe2x80x2) 
xe2x80x83wherein
Raxe2x80x2 is a group of the formula 
xe2x80x83wherein
Rxe2x80x2 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl, phenyl or aralkyl, which optionally has a substituent on the ring,
R1 is hydrogen, alkyl, or cycloalkyl, cycloalkylalkyl , phenyl or aralkyl, which optionally has a substituent on the ring, or
Rxe2x80x2 and R1 in combination form, together with the adjacent nitrogen atom, a group forming a heterocycle optionally having, in the ring, oxygen atom, sulfur atom or optionally substituted nitrogen atom,
R2 is hydrogen or alkyl,
R3 and R4 are the same or different and each is hydrogen, alkyl, aralkyl, halogen, nitro, amino, alkylamino, acylamino, hydroxy, alkoxy, aralkyloxy, cyano, acyl, mercapto, alkylthio, aralkylthio, carboxy, alkoxycarbonyl, carbamoyl, mono- or dialkylcarbamoyl or azide, and
A is a group of the formula 
xe2x80x83wherein R10 and R11 are the same or different and each is hydrogen, alkyl, haloalkyl, aralkyl, hydroxyalkyl, carboxy or alkoxycarbonyl, or R10 and R11 show a group which forms cycloalkyl in combination and l, m and n are each 0 or an integer of 1-3,
Rb is a hydrogen, an alkyl, an aralkyl, an aminoalkyl or a mono- or dialkylaminoalkyl; and
Rc is an optionally substituted heterocycle containing nitrogen,
an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(4) The agent for the prophylaxis and treatment of liver disease of (1) above, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.
(5) The agent for the prophylaxis and treatment of liver disease of (1) above, wherein the compound having a Rho kinase inhibitory activity is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and/or a pharmaceutically acceptable acid addition salt thereof.
(6) The agent for the prophylaxis and treatment of liver disease of any of (1) to (5) above, wherein the liver disease is caused by activation of hepatic stellate cell.
(7) The agent for the prophylaxis and treatment of liver disease of any of (1) to (6) above, wherein the liver disease is at least one selected from the group consisting of hepatitis, hepatic fibrosis, hepatic cirrhosis and hepatic cancer.
(8) An activation inhibitor of hepatic stellate cells, which comprises a compound having a Rho kinase inhibitory activity.
(9) The activation inhibitor of hepatic stellate cells of (8) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), particularly a compound of the formula (Ixe2x80x2), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(10) The activation inhibitor of hepatic stellate cells of (8) above, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.
(11) The activation inhibitor of hepatic stellate cells of (8) above, wherein the compound having a Rho kinase inhibitory activity is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)-cyclohexane and/or a pharmaceutically acceptable acid addition salt thereof.
(12) A pharmaceutical composition for the prophylaxis and treatment of liver disease, which comprises a compound having a Rho kinase inhibitory activity and a pharmaceutically acceptable carrier.
(13) The pharmaceutical composition for the prophylaxis and treatment of liver disease of (12) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), particularly a compound of the formula (Ixe2x80x2), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(14) The pharmaceutical composition for the prophylaxis and treatment of liver disease of (12) above, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b)pyridin-4-yl)-4-l(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.
(15) The pharmaceutical composition for the prophylaxis and treatment of liver disease of (12) above, wherein the compound having a Rho kinase inhibitory activity is (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane and/or a pharmaceutically acceptable acid addition salt thereof.
(16) The pharmaceutical composition for the prophylaxis and treatment of liver disease of any of (12) to (15) above, wherein the liver disease is caused by activation of hepatic stellate cell.
(17) The pharmaceutical composition for the prophylaxis and treatment of liver disease of any of (12) to (16) above, wherein the liver disease is at least one selected from the group consisting of hepatitis, hepatic fibrosis, hepatic cirrhosis and hepatic cancer.
(18) A method of the prophylaxis and treatment of liver disease, which comprises administering an effective amount of a compound having a Rho kinase inhibitory activity to a patient.
(19) The method of the prophylaxis and treatment of liver disease of (18) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the formula (I), particularly a compound of the formula (Ixe2x80x2), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(20) The method of the prophylaxis and treatment of liver disease of (18) above, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.
(21) The method of the prophylaxis and treatment of liver disease of (18) above, wherein the compound having a Rho kinase inhibitory activity is a (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, and/or a pharmaceutically acceptable acid addition salt thereof.
(22) The method of the prophylaxis and treatment of liver disease of any of (18) to (21) above, wherein the liver disease is caused by activitation of hepatic stellate cell.
(23) The method of the prophylaxis and treatment of liver disease of any of (18) to (22) above, wherein the liver disease is at least one selected from the group consisting of hepatitis, hepatic fibrosis, hepatic cirrhosis and hepatic cancer.
(24) Use of a compound having a Rho kinase inhibitory activity for the production of an agent for the prophylaxis and treatment of liver disease.
(25) The use of (24) above, wherein the compound having a Rho kinase inhibitory activity is an amide compound of the following formula (I), particularly a compound of the formula (Ixe2x80x2), an isomer thereof and/or a pharmaceutically acceptable acid addition salt thereof.
(26) The use of (24) above, wherein the compound having a Rho kinase inhibitory activity is a compound selected from the group consisting of (+)-trans-4- (1-aminoethyl)-1-(4-pyridylcarbamoyl)-cyclohexane, (+)-trans-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)cyclohexanecarboxamide, (R)-(+)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide and (R)-(+)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(1-aminoethyl)benzamide, and/or a pharmaceutically acceptable acid addition salt thereof.
(27) The use of (24) above, wherein the compound having a Rho kinase inhibitory activity is a (+)-trans-4-(1-aminoethyl)-1-(4-pyridylcarbamoyl)cyclohexane, and/or a pharmaceutically acceptable acid addition salt thereof.
(28) The use of any of (24) to (27), wherein the liver disease is caused by activation of hepatic stellate cell.
(29) The use of any of (24) to (28), wherein the liver disease is at least one selected from the group consisting of hepatitis, hepatic fibrosis, hepatic cirrhosis and hepatic cancer.
(30) A commercial package comprising a pharmaceutical composition for the prophylaxis and treatment of liver disease of any of (12) to (17) above, and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for the prophylaxis and treatment of liver disease.